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Antisense oligonucleotides (AONs) represent a potential therapeutic approach to treat inherited retinal diseases, which lead to progressive vision loss due to pathogenic variants in retinal genes. Whilst AONs offer a powerful tool to correct genetic defects at the RNA level, their efficacy and safety rely on the design and chemical modifications of these molecules. Understanding these details are crucial to fully maximize their therapeutic potential.
A recent study led by Irene Vázquez-Domínguez (Department of Human Genetics) and Alex Garanto (Department of Pediatrics & Department of Human Genetics), in collaboration with researchers from Radboud University Medical Center (Rob Collin) and Amsterdam University Medical Centers (Céline Koster), was published in Nucleic Acids Research. The research team explored how AONs with different chemical modifications perform when delivered to the retina. Specifically, they compared three chemical modifications currently used in clinical trials for other diseases: 2’-O-methyl-phosphorothioate (2’-OMe/PS), 2’-O-methoxyethyl-phosphorothioate (2’-MOE/PS), and phosphorodiamidate morpholino oligomers (PMO). Their goal was to assess how each modification influences the distribution, efficacy, and safety of AONs in the eye.
Targeting genes that are exclusively expressed in the retina, the researchers evaluated the efficacy of the AONs in both lab-grown cells (in vitro) and live animals (in vivo). The results were quite revealing: both 2’-OMe/PS and 2’-MOE/PS AONs showed comparable safety and efficacy profiles, positioning them as promising candidates for future therapies. However, the PMO chemistry, particularly when modified for in vivo applications, exhibited significant toxicity in the eyes of treated animals, raising substantial safety concerns.
The study underscores the critical role that chemical modification plays in determining the efficacy and safety of AONs. Among the three, 2’-MOE/PS modification emerged as the most promising, offering the best balance between efficacy and safety. This research thereby provides valuable insights that will support the development of safer and more effective AON-based therapies for retinal diseases in the future.
Publication
Irene Vázquez-Domínguez, Alejandro Allo Anido, Lonneke Duijkers, Tamara Hoppenbrouwers, Anita D M Hoogendoorn, Céline Koster, Rob W J Collin, Alejandro Garanto. Efficacy, biodistribution and safety comparison of chemically modified antisense oligonucleotides in the retina, Nucleic Acids Research (2024), gkae686. PMID: 39119918.
Photo left to right: Irene Vázquez-Domínguez, Lonneke Duijkers, Anita Hoogendoorn, Rob Collin, Alejandro (Alex) Garanto
